Abstract A universal influenza vaccine that is capable of protecting against all strains of influenza is a high priority. The Centers for Disease Control & Prevention (CDC) estimate the economic impact of seasonal influenza in the United States to range from $10 to $16 billion and pandemic influenza to range from $71.3 to $166.5 billion. The proposed research directly addresses the limitations of both pandemic and seasonal flu vaccines. Versatope has developed a unique influenza M2e antigen construct, expressed in Escherichia coli and derived from recombinant outer membrane vesicles (rOMVs) or M2e-rOMVs, that is potentially effective against all strains of influenza. These rOMVs that display influenza M2e proteins represent a potentially safe and simple subunit vaccine delivery platform that will increase the range of protection against multiple strains of pandemic and seasonal influenza and reduce the overall economic impact. We are the first company to leverage our OMV to use one vaccine candidate to express heterologous antigens (proteins from a different organism) and provide 100% protection against several strains of influenza in mice having different genetic backgrounds and different species of animals (mice and ferrets). The unique rOMVs we created do not trigger a pyrogenic response in human blood, but induce effective immune protection against H1N1 in BALB/c mice, H1N1 in C57BL/6 mice, and H3N2 in BALB/c mice. The OMV vaccine delivery is innovative because our strain has been genetically engineered to detoxify lipopolysaccharide (LPS) more than 1000-fold (they do not require chemical extraction of LPS to detoxify the final product) and to increase OMV formation more than 30-fold compared to the parental strain of pro-biotic bacteria. To demonstrate the societal impact and commercial opportunity of the M2e-rOMVs, we applied these protection parameters to CDC epidemiologic models of pandemic influenza and calculated a 50% a reduction in infection, hospitalization and death rates. Collectively, these results underlie the justification and commercial opportunity for the proposed research. Our proposed research program is primarily translational, the outcome of which will guide the path toward a viable single-dose vaccine for pandemic influenza A. The development of this new rM2e-rOMV derived from chromosomal integration will enable large-scale production suitable for non-clinical development and toxicology, clinical studies, and commercial development. The specific focus for the current proposal is the development of new rOMV strains capable of protection against pandemic influenza and suitable for fermentation on a large scale. We will also identify the minimum dose required for immunogenicity to initiate safety/toxicity studies. The M2e vaccine candidate expressed in OMVs that we have developed is a significant improvement over traditional influenza vaccine candidates because immunity is imparted to multiple strains and the OMVs have lower reactogenicity and inflammatory responses compared to other approaches.